Anti-platelet therapy has been shown to reduce clinical ischemic events and improve outcomes for acute coronary syndrome (ACS) patients. Currently, the approved anti-platelet products include aspirin and thienopyridines, such as clopidogrel and ticlopidine. One of the most widely prescribed thienopyridines is clopidogrel, which is also known as Plavix®.
Thienopyridines such as clopidogrel irreversibly inhibits P2Y12 receptors which play an active role in platelet activation. In the normal state, when blood vessels are damaged, platelet activation mediated by P2Y12 receptors play an important role to arrest bleeding at the site of injury. In a diseased state, platelet activation leads to vascular occlusion and ischemic damage. Thus, P2Y12 receptors antagonists play a key role in antiplatelet therapy in assisting to prevent coronary artery disease and for the immediate treatment of ACS and percutaneous coronary intervention (PCI).
Physicians often prescribe dual anti-platelet therapy, which include aspirin and a thienopyridine, such as clopidogrel for patients who have been diagnosed with ACS or for patients who are showing symptoms associated with ACS as a first line treatment. Pending further examinations, these patients may continue with this treatment or receive other treatments such as coronary artery bypass grafting (CABG) and PCI. Consistent with this practice, current American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend immediate initiation of dual anti-platelet therapy of clopidogrel and aspirin after a patient is diagnosed with ACS. Similarly, patients that have received a bare metal stent or drug-eluting stent are also put on the dual clopidogrel and aspirin therapy for an extended period of time to prevent an ischemic event. For instance, a post hoc analysis of a blinded, placebo-controlled trial suggest a benefit of platelet activity inhibition in terms of decreased thrombotic events prior to CABG (Fox K A et. al, Circulation. 2004; 110; 1201-08). For many patients, this dual anti-platelet therapy provides tremendous clinical benefits, and minimizes the risks of ischemic events, such as heart attack and stroke.
Dual anti-platelet therapy, however, has drawbacks. Cessation of clopidogrel may increase the incidence of ischemic events in the short-term due to a “rebound” effect of platelet activation (Brilakis E S et al, J Am Coll Cardiol. 2007 Jun. 5; 49(22):2145-50; Ho P M et al, JAMA. 2008 Feb. 6; 299(5):532-9).
In addition patients receiving dual anti-platelet therapy experience an increased incidence of blood transfusions and bleeding complications while undergoing surgery and other invasive procedures. This is particularly true for ACS patients who often receive surgery, such as CABG and PCI, and other invasive procedures, such as implantation of a bare metal stent (BMS) or drug-eluting stent (DES). Because aspirin and thienopyridines are irreversible, long-acting platelet antagonists reversal of the inhibition of platelet function occurs only as new platelets are generated and therefore even after discontinuation, their effect can lasts several days before being completely eliminated.
Thus, for patients under dual therapy who also require surgery such as CABG sustained platelet inhibition poses an unacceptable risk of bleeding. Consequently, it has been recommended by the ACC/AHA and the Society of Thoracic Surgeons (STS) guidelines to cease thienopyridine therapy prior to undergoing non-emergent cardiac surgical procedures to minimize bleeding risks. Thus, patients are often required to stop dual anti-platelet therapy and wait for five to seven days before any invasive procedures can be performed.
On the other hand, even though clopidogrel treatment prior to CABG does increase bleeding due to its irreversibility, platelet P2Y12 inhibition does appear to prevent ischemic events in patients requiring CABG. As a result, physicians often face the difficult choice of discontinuing clopidogrel and aspirin prior to surgery and risking a potential ischemic event in the unprotected perioperative period or delaying surgery until the time at which clopidogrel is no longer required.
Currently, no ultra short-acting platelet inhibitors are available that allow maintenance of platelet inhibition before an invasive procedure without increasing bleeding complications at the time of an invasive procedure. Potentially, effective platelet inhibition with an ultra short-acting platelet inhibitor during the period of clopidogrel withdrawal may protect patients from ischemic events and also preserve normal hemostasis at the time of surgery.
Therefore, a need exists for a new therapy for patients who are undergoing surgery (this includes therapy prior to, during, and post) or other invasive procedures, and who have a need for anti-platelet therapy. This new therapy maintains platelet inhibition at acceptable levels while allowing for rapid restoration of platelet function after discontinuation so that patients may undergo surgical procedures without increasing the risk of bleeding complications.
In addition, a need exists for a new therapy for patients who, for whatever reason, cannot be administered thienopyridines, such as clopidogrel or Plavix®, or cannot receive orally administered antiplatelet therapies.